3,5-Substituted-1,2,4-oxadiazole inner quaternary ammonium salts

ABSTRACT

New antimicrobial agents of the formula   where R1 includes halophenyl, loweralkyl, phenyl, nitrophenyl, dinitrophenyl, nitrofuryl, and nitrothienyl; R2 includes hydrogen and loweralkyl; and Nhet includes a heterocyclic moiety bonded through a nitrogen thereof which is sufficiently basic to form quaternary ammonium salts.

United States Patent [191 Von Esch et al.

[451 Sept. 23, 1975 3,5-SUBSTITUTED-1,2,4-OXADIAZOLE INNER QUATERNARYAMMONIUM SALTS [75] Inventors: Anne Mary Von Esch, North Chicago; AldoJoseph Crovetti, Lake Forest, both of Ill.

[73] Assignee: Abbott Laboratories, North Chicago, 111.

22 Filed: Dec. 18, 1972 21 Appl. No.: 316,189

Related U.S. Application Data [62] Division of Ser. No. 85,747, Oct. 30,1970, Pat. No.

Primary Examiner-D0nald G. Daus Assistant Examiner-Mary C. VaughnAttorney, Agent, or FirmGildo E. Fato; Robert L. Niblack [57] ABSTRACTNew antimicrobial agents of the formula 0 69 l s t- R,C N (6-09 where R,includes halophenyl, loweralkyl, phenyl, nitrophenyl, dinitrophenyl,nitrofuryl, and nitrothienyl; R includes hydrogen and loweralkyl; and Nincludes a heterocyclic moiety bonded through a nitrogen thereof whichis sufficiently basic to form quaternary ammonium salts.

1 Claim, No Drawings l 3,5-SUBSTITUTED-1,2,4-OXADIAZOLE INNER QUATERNARYAMMONIUM SALTS i This is a division of application Ser. No. 85,747,filed Oct. 30, 1970, now U.S. Pat. No. 3,725,424.

DISCLOSURE OF THE INVENTION This invention relates to new compoundshaving antimicrobial utility and whiich have the formula wherein R isloweralkyl, phenyl, nitrophenyl, dinitrophenyl, nitrofuryl, andnitrothienyl; R is hydrogen and loweralkyl; and N is a heterocyclicmoiety bonded to the carbon atom on the 5-position of the oxadiazolethrough a nitrogen atom thereof, which nitrogen is sufi'iciently basicto quaternize. Such groups that are suitable include pyridinyl, halo andloweralkyl substituted pyridinyl; pyrimidinyl, halo and loweralkylsubstituted pyrimidinyl, quinolinium, halo and loweralkyl substitutedquinolinium, isoquinolinium, halo and loweralkyl substitutedisoquinolinium, thiazolium, isothiazolium and loweralkylthiazolium.

As used herein, the term loweralkyl is intended to include those alkylgroups having from 1 to 4 carbon atoms, e.g., methyl, ethyl, propyl andbutyl. The term halo is meant to include halogen substitutions whereinthe halogen substituent is chlorine, bromine, or iodine.

The novel salts of this invention which are described below in detailpossess valuable antibiotic activity against organisms such for exampleas Staphylococcus aureus. Furthermore, activity has been established fora number of these new compounds (as shown below in Table II) against thepathogenic fungi of the genus Trichomona especially T. vaginalis.

These new compounds are utilized as the inner quaternary salt, and beingsuch are somewhat water soluble, at least more so than non-salt organiccompounds of an equivalent molecular weight. They may be used in humanand veterinary medicine in the form of pharmaceutical compositionscontaining one or more pharmaceutical carriers or excipients suitable,for example, for oral, topical, rectal, intravaginal or parenteraladministration. They may be used alone or together with other medicinalagents. The compositions are preferably in unit dosage form and eachdosage unit preferably contains 0.5 to 500 mg. of the active compound,advantageously 5 to 250 mg. for example.

For administration as solid oral preparations such as tablets orcapsules, conventional carriers may be employed, for example, gelatin,lactose, starch, talc, magnesium stearate, hydrogenated oils,polyglycols, etc. The compositions may also take the form of liquid oralpreparations for ingestion such as solutions, syrups, elixirs,emulsions, etc., which may contain suspending, emulsifying, stabilizingand preserving agents and may also contain acceptable sweetening,flavoring or coloring agents. The compounds may be prepared for localapplication to the mucous membranes of the nose and throat and may takethe form of liquid sprays or powder insufflations, nasal drops, throatpaints or similar preparations. Formulations for external applicationsmay be prepared in oily, aqueous or powdered media in the form ofconventional skin paints, lotions, creams, ointments, aerosols, dustingpowders, etc. Suppositories and pessaries may contain a conventionalbase, e.g., oil of theobroma, polyglycols, glycogelatin bases togetherwith surface active agents if required. The injectable preparations maytake the form of aqueous or oily solutions, emulsions, suspensions orsolidss for re constitution before use. Suitable vehicles include, forexample, sterile, pyrogen-free water, parenterally acceptable oils, oilyesters or other non-aqueous media such as propylene glycol, if desiredcontaining suspending, dispersing, stabilizing, preserving,solubilizing, emulsifying or buffering agents.

The compounds of this invention are prepared most advantageously in thefollowing manner. A compound of the formula is admixed with N,,,., whereR and N are as hereinbefore defined, and an appropriate acid anhydride.By appropriate acid 'anhydride, it is meant that if R is intended to behydrogen, then a mixed acetic-formic anhydride should be used, and if Ris to be isopropyl, then 2,2-dimethyl-acetic anhydride should beemployed. While the reaction can be carried out without the use ofadditional solvent, preferably an inert solvent such as nitromethane,ethanol or aqueous dimethylsulfoxide is used to insure a more completereaction with higher yields. By the term inert solvent, is meant asolvent that is not reactive toward reactants or products.

The reaction can be carried out at the reflux temperature of theadmixture; yet it is preferred that the reaction temperature bemaintained between, 25-75 C. The course of the reaction can easily befollowed by observing the formation of product which is a brightlycolored solid. After reaction is deemed complete, which is usually thecase after 12 hours, the solid product is collected and washed, forexample with cold, i.e., less than 0 C. ethanol.

The following specific examples will further serve to illustrate thisinvention.

EXAMPLE I In this method of preparation, the reactants act as mutualsolvents, no additional solvent being added. Thus, 9.2 g. of5-chloro'methyl-3-(5-nitro-2-furyl)- 1,2,4-oxadiazole was dissolved in amixture of 10 ml. of acetic anhydride and 25 m1; of pyridine. Thesolution was heated overnight at 55 C. In the course of the reaction,the product crystallizes as a bright yellow solid. The compound wasfiltered and washed with ethanol. The yield is 12.5 g., m.p. 265 C(dec). For analysis the compound can be recrystallized from nitromethaneor ethanol.

Analysis Calcd. for C,.,I-I N O :C,53.5 1%; I-I,3.21%; N,l7.82%.

Found: C,53.24%; l-l,3.22%; N,l7.83.

EXAMPLE 2 In this preparation, additional solvent herein beingacetonitrile is added. Thus, 5.0 5. (0.0218 mole) of 5- 3 chloromethyl-3-( 5-nitro-2-furyl )-l ,2,4-oxadiazole, 2.03 g. (0.0218 mole)rof4-methylpyridine, 2.80 g. of acetic anhydride in 25 ml. acetonitrileheated at reflux for 2 hours. The reactionis cooled, the productfiltered, washed with acetonitrile and alcohol successively. Afterhaving been dried, there was about 3 grof crude product having a meltingpoint of greater than 300 C.

Ex. M.P. Solvent for No. R. N he R: in C Recrystallization yield 63 3 CHCH;, 240242 (dec) ethanol 733 4 CH;, 1% (dec) ethanol 82.6

G9 5 NO. -CH,, 272-277 (dec) mtromcthune 71.5

2 (B 6 Q CH,, 260 (dec) ethanol 75.5

63 7 NO: CH;, 248-250 (dec) ethanol 83.3

8 NO CH, 265 (dec) nitromcthane 97.3

9 NO. CH- CH;, 243245 (dec) nitromethzmc 98 (B 10- NO CH-; CH CH 253ethanol 80.5

u N0. Q CH:, 247-249 (dec) ethanol 72 12 N@@ -cH,, 255-258 (dec)nitromcthane CH 13 NO U CH --CH;, 300 (dec) nitromethane 73 l4 NO CH=235 (dec) nitromethane 37 l5 bio -1E3- N CH, CH,, 245-247 (dec)nitromethane 89 5 16 NO.;@ CH,, 295 (dec) nitromethane 67 CH2! I i! 17NO U- CH; 245-247 (dec) nitromethane 69 CH3 (9 18 NO. CH CH;, 290 (dec)nitromethanc 99 I 19 NO: N CH CH 300 (dcc) ethanol 5 l ,5

2o Nmm CH,, 255 ((160) nitromcthane 41.8

CH3 2] NO ,U CH;, 300 (doc) nitromethanc 24 Q9 22 NO (H; 247-249 (dec)nitromethunc 63.7

23 bio -Q. f 2 (H,, 283-284 (dec) DMSO+H. ,O 45

CONH 24 NO. coNH. -CH 270 (dcc) pmso 0 The5-chloromethyl-3-(3,5-dinitrophenyl )-l ,2,4- oxadiazole, which is usedto prepare the compound of this invention disclosed in Example 6, isprepared in the following manner:

g. of 3,S-dinitrophenylamidoxime is refluxed in ml. ofchloroacetylchloride for two hours. The excess acid chloride is removedunder reduced pressure. The oily solid is then suspended in 50 ml. ofbutanol and refluxed for six hours. Upon cooling, the productcrystallizes from the solvent, M.P. l26-8 C.

Analysis Calcd. for C H ClN O C,37.99; H,l .78; H,l9.66.

Found: C,38.l6; H,l.77; N,l9.75.

The compounds of this invention have demonstrated in vitro utilityagainst Staphylocossus aureus Smith and such activity is illustrated inTable I in which the minimum inhibitory concentration is set forth inparts per million.

Table II illustrates the in vitro activity of the compounds of thisinvention against Trichomonas vaginalis in parts per million.

Table ll Compound of Minimum Inhibitory Example Concentration Weclaim: 1. The compound of the formula

1. THE COMPOUND OF THE FORMULA